4-amino-5-phenyl-1-pentene



United States Patent 3,210,424 4-AMTNO-S-PHENYL-ll-PENTENE Dominic Donald Micucci, Havertown, Pan, assignor to Richardson-Merrell Inc., New York, N.Y., a corpora- 3,210,424 Patented @et. 5, 1965 lice EXAMPLE One hundred and twerity-five milliliters of bromine was added to a solution of 360 grams of sodium hydroxide in 3 liters of water and cooled to a temperature of ti f D l 5 C; To this mixture was added alpha-allyl-beta-phenyl- No Drawing. Filed Apr. 19, 1963, Ser. No. 274,348 propionarnide (285 grams, 1.5 mole). After stirring for 2 Claims 259-5703) one hour at 0 (3., the mixture was allowed to warm to This invention relates to amphetamine derivatives havroom tempieratmfsfl g occasiorial i ing new and valuable combinations of pharmacological b f. g z i rOIOm E; Surnnb properties. In a particular aspect, this inventionrelates was continue Or.an a 9 one an to 4-amino-5-phenyl-1-pentene and its acid addition salts, The product mlxture i extracted Wlth methyl. 6t the extract was washed with percent hydrochlorlc acid and to amethod for their preparat1on. 1 d th th 1 th f 7 d d The prepartion of 4-amino-5-phenyl-l-pentene is conan h g Y e .g 1011 5 5 1 veniently accomplished by treatment of alpha-allyl-hetai ig i; one am so w g e phenylpropionamide with bromine or chlorine and alkali y 6 en ig f g pro ,1 i Was am under Hofmann rearrangement conditions: ed i extlacted l f e ether eimact was dried and fractionally distilled in vacuo. 4-am1no-5- phenyl l-pentene was recovered as a distillate fraction, n =1.52l5. CH CH-CONH A portion of the 4-amino-5-phenyl-l-pentene was con- CHFCHZCHZ verted to the hydrochloride salt in the usual manner. The salt was recrystallized from ethanol-diethyl ether, melting point 150 C. to 160 C. Elemental analysis was A in accord with the designated structure.

CH2 OH 1161 4-amino-5-phenyl-l-pentene may be administered orally H2 CI'I=CI'I2 or by injection. The following are illustrative of pharmaceutical dosage forms suitable for administration of the (1) compound:

(a) Fifty (50) grams of 4-amino-5-phenyl-l-pentene 3O hydrochloride is mixed-intimately with 25 grams of corn starch and 175 grams of lactose. The mixed powders OHZTOHzCHZ of granulated with 10 percent starch paste and forced through a 12-mesh stainless steel screen. The granulation (11 r is dried thoroughly at a temperature not exceeding 40 C. and then forced through a 16-mesh stainless steel screen. Five (5) grams of talc and 2.5 grams of mag- In contrast to amphetamine and other related drugs, nesiurn stearate are added and mixed by tumbling with 4-amino-5-phenyl-1-pentene has oral analgesic activity in the granulation. The granulation is then compressed into rats and mice at dose levels considerably below those pro- 40 1,000 tablets, each containing 50 milligrams of the active ducing overt side effects. This compound also exhibits compound. hypotensive activity, and anticonvulsant and anorexic ac- (b) Fifty (50) grams of 4-amino-5-pheny1-l-pentene tivities at doses producing little or no symptomatology. hydrochloride is mixed intimately with 250 grams of lac- Anti-inflammatory activity was evident at higher doses. tose and 1.5 grams of calcium stearate. The mixture is The Straub Tail test, together with other pharmacology, forced through a 40-mesh stainless steel screen, and is suggests that 4-amino-5-phenyl4-pentene is not opiatethen filled into 1,000 gelatin capsules, each containing like. 4-amino-5-phenyl-l-pentene is a promising nonmilligrams of the active compound. narcotic analgesic agent. (0) Ten (10) grams of 4-amino-5-phenyl-l-pentene Oral analgesic doses (ED in mice produced no hydrochloride, 0.9 gram of methylparaben, 0.1 gram of overt symptomatology. Xylopropamine and d-amphetpropylparaben, and 5 grams of sodium chloride are disamine produced analgesia only at doses at or near those 50 solved in 900 milliliters of water for injection and brought showing definite CNS stimulation. The compound is to a volume of 1 liter with water for injection. The solualso effective in lowering blood pressure in anesthetized tion is filtered through hardened filter paper, and is then normotensive dogs. sterilized by filtration through Selas candle. The solution A summary of some of the biological testing of 4- is then filled, under aseptic. conditions, into sterile S-milliamino-S-phenyl-l-pentene is contained in Tables I and II. liter ampul vials. The vials are capped with sterile rubber closures and sealed with aluminum seals. The final con- 1 M u i, Avakifln. Dietrich, Beiler, and centration of active compound in the solution is 10 millir I F" l iihfirl;2%?1i%f 1i%, %s2 ?isi3? grams p hh T able I Dose Range (mice) Acute Toxicity Anticonvnlsant Analgesia Antiinflamma- Hypotensive (mice) tory (mice) (mice) tory (rats) (dogs) 4-a1nino-5-phenyl-l-pcntenc-HC1.- No overt symptoms below Ill 50 120. EDm 1?.0. 84 ED50 P.0. 25 Active at Active hypomg./kg. orally; at higher 260 nag/kg. nigJkg. rug/kg. mgJkg. teusive. doses symptom profile consists of CNS stimulation.

1 Dose producing death in 50 percent 01 animals tested. 2 Per oral route of administration. 3 Dose exerting pharmacological eifect on 50 percent of animals tested.

T able I1 Analgesic Activity Mouse LD Mouse LD (mg/kg.) orally (mg/kg.) LV. Mouse Hot Mouse Writhing Mouso Tail Randall Sollito Plate 1 EDmo EH50 (mg'./kg.) Clamp ED ED50 (mg/kg.) (mg/kg.) orally orally (mg./kg.) LV. orally 4-a1nin0-5-phenyl-1-pentene- 200 30 28 13 140 HCI. (208-325) (24-3 (19-40) (8. 1-20. 8) d-Arnphetaminc sulfate 33 10 2. 6 4. 1

(21-52) (8-11) (0. 9-5. 7) (2. 7-6. 0) Xylopropamine hydrochlor- 220 23 26 0. 6

ide. (154-300) (17-30) (20-32) (0. 15-2. 4) d-Propoxyphene hydroehlor- 255 21 4. 7 48 ide. (200-325) (22-28) (15-32) (3. 4-0. 4) Codeine phosphate Approx. 400 so 6. 8 6. 5 98 (67-111) (4. 6-10. 1) (3. 9-10. 7) Acetylsalicylic acid Approx. 2,000 70 138 270 1 Minimum dose producing pharmacological effect in 100 percent of animals tested. 2 Na Salicylate active only in toxic dose range.

What is claimed is: 20 3,052,721 9/62 Bernstein et a1. 260570.5 X 1. Compounds of the group consisting of 4-an1ino-5- 3,068,233 12/62 Ka sfir 61 E1 260-5705 X phcnyl-l-pentene and the acid addition salts thereof. 1 1 10/63 K5115 26G553 X 2. 4--an1in05-phenyl-1-pcntene hydrochloride. OTHER REFERENCES r V 1: References ciged by me Emminm, 25 Houben Weyl. Methoden der Organischcn Cherrnc,

UNITED STATES PATENTS volume XI/l, pages 859 (1957).

CHARLES B. PARKER, Primary Examiner.

IRVING MARCUS, Examiner. 

1. COMPOUNDS OF THE GROUP CONSISTING OF 4-AMINO-5PHENYL-1-PENTENE AND THE ACID ADDITION SALT THEREOF. 